ASH 2018 – MMRF CoMMpass Study Findings #2

Saturday at ASH saw 6 oral presentations on data from our landmark CoMMpass Study! Much of the data presented today advanced our understanding of the mechanisms that drive myeloma cell growth and survival as well as the mechanisms that drive relapse. The information presented today is another step forward in providing myeloma patients the right treatment based on their own specific disease profile. The information presented ranged from predictors of high-risk disease to light chain amyloidosis.

Our colleagues at TGen in Phoenix, Arizona analyzed CoMMpass data from 100 patients who had their genome sequenced at the time of diagnosis and again at relapse. When comparing the genome from diagnosis to relapse, they found 7 different genes that were normal at diagnosis had mutated (ie, a defect or error) at the time of relapse. These genetic changes were mostly the loss of cell cycle regulators (proteins involved in normal cell division).  Drugs that target the cell cycle could be a new class for the treatment of myeloma since these results show that progression of myeloma is driven by changes in cell cycle pathways. Drugs in this class (ie, the cell cycle inhibitors) are already approved as treatments for other cancers. Our MyDRUG trial, the first platform trial in multiple myeloma, has a treatment arm that includes the addition of cell cycle inhibitors for relapsed patients with these types of genetic mutations. Find out more here: https://themmrf.org/mydrug/

One of the biggest findings from the CoMMpass study is that multiple myeloma is made up of about 12 different and distinct subtypes of disease. But what is not understood—and what investigators at TGen investigated—is what genetic features underlie these subtypes. Patient bone marrow samples from CoMMpass underwent genomic sequencing using a variety of techniques. The results showed:

  • A specific high-risk population of myeloma patients exhibits the complete loss (or “double-hit”—that is, both copies of the gene are no longer functional) of the TP53 gene (this is the gene found on chromosome 17 and typically noted as deletion 17p [del17p]) is associated with a poor outcome
  • Certain genetic mutations (ie, defects or errors) are associated with a subset of patients who have the chromosomal translocation t(11;14)

Investigators at Icahn School of Medicine at Mount Sinai—led by Dr. Alessandro Lagana—presented their work on the expression of a protein on cells called HLA-E and its potential association with high-risk disease.The HLA-E protein is responsible, in part, to dampening the immune response to cancer by inhibiting the activation of certain immune cells. Dr. Lagana and colleagues looked at the expression of this protein from bone marrow samples from 436 newly diagnosed myeloma and untreated patients enrolled in the CoMMpass study. Based on their analysis, they found that HLA-E expression was high in 32 patients, medium in 296 patients, and low in 120 patients. Patients with high expression of this protein:

  • Had a shorter time before disease progression compared to patients with a medium or low expression pattern
  • Were associated with a worse prognosis due to the inhibition of the immune response against myeloma cells

This information could help clinicians select specific immune-targeted therapies for patients with high expression of this protein. For now, the HLA-E marker remains experimental.

We switch gears for a bit to focus on light chain amyloidosis (AL). AL is when cancerous plasma cells (the cells that produce antibodies) produce misfolded light chains (a part of the antibody) that then become lodged in tissues of the body such as the heart or kidneys. Dr. Dirk Hose from Heidelberg, Germany presented his work on whether there are any genetic features of amyloidosis that distinguish it from monoclonal gammopathy of undetermined significance (MGUS), smoldering myeloma (SMM), and active myeloma that might aid in prognosis.

He found that prognosis is determined by specific amyloidosis factors (such as organ involvement, amount of free light changes, and cardiac function), by cancerous plasma cell factors (such as a high growth rate, presence of genetic risk factors) and other factors that represent the amount of cancer cells in the body like M-protein levels. Based on these results, AL is considered an early plasma cell abnormality with an unstable and toxic light chain.

The final CoMMpass abstract for the day investigated the genetic profiles of circulating tumor cells (CTCs) with patient-matched bone marrow cells to determine how myeloma cells spread from the bone marrow and into the blood as the disease progresses. Investigators from Spain isolated CTCs and bone marrow cells from 34 patients and analyzed their genetic makeup using various methodologies. Gene expression between the CTCs and matched bone marrow samples were similar and only 45 genes were found to be deregulated in CTCs. These genes were shown to be clinically meaningful using CoMMpass samples. They relate to a more aggressive disease and may represent targets for new drugs that overcome disease progression and dissemination.